During B cell development in the bone marrow (BM) random immunoglobulin (Ig) gene rearrangement[unreadable] generates a highly diverse antibody repertoire, including B cells that express autoreactive antibodies.[unreadable] Experiments with transgenic mice indicate that three mechanisms - receptor editing, deletion and anergy -[unreadable] account for silencing of self-reactive B cells and ensure self-tolerance. We have recently shown that the[unreadable] majority of antibodies expressed by developing B cells in the BM of healthy human donors recognize selfantigens,[unreadable] but self-reactive antibodies are lost from the repertoire at two checkpoints: at the immature B cell[unreadable] stage in the BM and in the periphery before maturation into naive immunocompetent B cells. Autoantibodies[unreadable] can also be generated by random somatic hypermutation of Ig genes during active immune responses, but[unreadable] the frequencies at which such autoantibodies are generated, how they are regulated and the role of B cell[unreadable] tolerance checkpoints during antigen-mediated B cell differentiation into memory and plasma cells are not[unreadable] known. The finding that large numbers of autoantibodies are produced under physiologic circumstances[unreadable] suggests that even small changes in the efficiency of autoantibody regulation at any stage during B cell[unreadable] development and differentiation would lead to increased susceptibility to autoimmunity. A hallmark of the[unreadable] systemic autoimmune disease lupus erythematosus (SLE) is the production of autoantibodies making this[unreadable] disease a useful model to study B cell tolerance checkpoints. Our preliminary data show that early[unreadable] checkpoints in B cell tolerance are abnormal in SLE, and that B cells emerging from the bone marrow of[unreadable] such patients are not adequately filtered to remove autoreactivity. The long-range goal of the proposed[unreadable] research project is (I) to define B cell tolerance checkpoints in healthy humans, (II) to determine where B cell[unreadable] tolerance is broken in SLE and (III) how B cell tolerance checkpoints are affected by therapy in patients with[unreadable] SLE.